Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.
Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.
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DOI：
10.1161/circep.123.011870
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发表时间：
2023-09
影响因子：
8.4
通讯作者：
Tinker, Andrew
中科院分区：
文献类型：
--
作者：
Specterman, Mark J.;Aziz, Qadeer;Li, Yiwen;Anderson, Naomi A.;Ojake, Leona;Ng, Keat-Eng;Thomas, Alison M.;Finlay, Malcolm C.;Schilling, Richard J.;Lambiase, Pier D.;Tinker, Andrew
缺氧缺血易致心房心律失常。心房atp敏感钾通道（KATP）在缺氧时的调节尚未探讨。我们研究了缺氧对KATP孔隙形成亚基缺失小鼠心房电生理的影响。检测全心KATP RNA表达。在分离的野生型（WT）、Kir6.1基因敲除（6.1-gKO）和Kir6.2基因敲除（6.2-gKO）小鼠心房肌细胞中记录全细胞KATP电流和动作电位。使用微电极阵列和程序化电刺激评估langendorff灌注心脏在常氧/缺氧条件下的心房有效不应期（ERP）、传导速度、波前路径长度（WFPL）和心律失常性。评估心脏组织学。所有KATP亚基RNA在人类心脏中的表达模式基本相同，而在小鼠中，Kir6.1和SUR2（磺脲受体亚基）在心室中的表达高于心房，Kir6.2和SUR1在心房中的表达高于心房。与WT相比，6.2-gKO心房肌细胞的甲磺丁胺敏感电流降低，动作电位去极化程度加深，上冲程减慢，峰值幅度降低。6.1 gko心房肌细胞动作电位持续时间延长，但未见其他离子通道基因表达改变或心房肌细胞肥大。在langendorff灌注的心脏中，与WT相比，两种KATP基因敲除小鼠的基线心房ERP延长，传导速度降低，无组织学纤维化。与基线相比，缺氧导致WT和6.1 gko心脏的传导速度减慢，ERP稳定，WFPL缩短，而6.2 gko心脏的WFPL稳定，因为ERP延长，传导速度减慢。在WT和6.1-gKO心脏中，Tolbutamide通过延长ERP逆转缺氧诱导的WFPL缩短。WT和6.1-gKO小鼠缺氧时程序性电刺激诱发的心房性心动过速与WFPL缩短相关。未见自发性心律失常。KATP阻断/缺失导致细胞和组织水平的心房电生理改变。Kir6.2基因整体敲除可防止缺氧诱导的心房WFPL缩短和程序性电刺激引起的心房心律失常。该机制可用于缺血性心房心律失常的治疗。
Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (KATP) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of KATP pore-forming subunits. Whole heart KATP RNA expression was probed. Whole-cell KATP current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout (6.2-gKO) murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed. Expression patterns were essentially identical for all KATP subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor subunit) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, 6.2-gKO atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both KATP knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in 6.2-gKO hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen. KATP block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.
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影响因子：
5
作者：
Glukhov, Alexey V.;Flagg, Thomas P.;Fedorov, Vadim V.;Efimov, Igor R.;Nichols, Colin G.
通讯作者：
Nichols, Colin G.
DOI：
10.1016/j.tem.2017.04.003
发表时间：
2017-08
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
--
作者：
Leonard CE;Hennessy S;Han X;Siscovick DS;Flory JH;Deo R
通讯作者：
Deo R
影响因子：
3.7
作者：
Finlay MC;Ahmed AK;Sugrue A;Bhar-Amato J;Quarta G;Pantazis A;Ciaccio EJ;Syrris P;Sen-Chowdhry S;Ben-Simon R;Chow AW;Lowe MD;Segal OR;McKenna WJ;Lambiase PD
通讯作者：
Lambiase PD
影响因子：
5
作者：
Fedorov VV;Glukhov AV;Ambrosi CM;Kostecki G;Chang R;Janks D;Schuessler RB;Moazami N;Nichols CG;Efimov IR
通讯作者：
Efimov IR